Centronuclear myopathy

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Note: "Centronuclear myopathy" includes "Myotubular myopathy", as outlined below.

Congenital Hereditary Myopathy
Classifications and external resources
ICD-10 G71.2
ICD-9 359.0
eMedicine neuro/76 

Contents

[edit] Definition of Myopathy

"Myo" means muscle and "pathos" means disease. Literally, a myopathy is a disease (medical condition) where the problem is at the muscle itself. Myopathies are certainly not the only medical conditions that can cause weakness. Weakness can be caused by medical conditions affecting sites outside of the muscle itself, including problems in the brain (such as stroke, cerebral palsy, multiple sclerosis), or problems in the spinal cord and/or nerve (such as polio and SMA, which is spinal muscular atrophy). But with a myopathy, the weakness is caused by problems within the muscle tissue itself. There are literally dozens of different myopathies.

Centronuclear myopathies are a group of myopathies where the cell nuclei are abnormally located at a position in the center of the skeletal muscle cells, instead of their normal location at the periphery. Although all forms of centronuclear myopathy (CNM) would be considered rare, probably the most commonly known form of CNM is Myotubular Myopathy (MTM).

[edit] Congenital Myopathies

Congenital conditions are present at birth. Centronuclear myopathies are generally considered to be congenital myopathies, since they often present at birth (this is particularly true of the X-linked myotubular myopathy form). Note that not all inherited conditions manifest themselves at birth, and thus "congenital" (clinically present at birth) is not synonymous with "hereditary" (genetic material, i.e. DNA, transmitted or capable of being transmitted from parent to offspring). Thus, not all congenital conditions are hereditary and not all hereditary conditions present congenitally. Among centronuclear myopathies, the X-linked myotubular myopathy form typically presents at birth, and is thus considered a congenital myopathy. However, some centronuclear myopathies may present later in life, and thus are not truly congenital. Thus, although centronuclear myopathies are generally classified as congenital myopathies, there are some non-congenital forms.

[edit] History: How the phrase "Myotubular Myopathy" came about

In 1966, Dr. Spiro (a New York City neurologist) published a medical report of a boy with myopathy where the muscle biopsy showed that the nuclei were located in the center of the muscle cells, instead of their normal location of the periphery. [1] Dr. Spiro thought that the appearance reminded him of the nucleus-in-the-center appearance during the “myotubular” stage of embryonic development. Thus, he coined the term "myotubular myopathy". Basically, he speculated that somehow embryonic muscle development was arrested during the myotubular phase, causing the myopathy. More than three decades later, it is still not fully understood whether this theory is correct regarding halted (or delayed) embryonic muscle development. Some research suggests that this theory (mechanism) may be true for infant-onset myotubular myopathy (mutations at the MTM1 gene on the X chromosome), but not true for the autosomal forms of centronuclear myopathy (CNM). [2] But other research suggests that this mechanism may be responsible for all forms of MTM and CNM. [3] Regardless of whether the myopathy truly is caused by arrest at the "myotubular" stage, for historical reasons the name "myotubular myopathy" persists and is widely accepted, particularly for the infant-onset X-linked form. [4]

When a genetic abnormality on the X chromosome was discovered as the involved DNA segment for a substantial percentage of individuals with the myotubular/centronuclear appearance on muscle biopsy, researchers decided to name the gene segment MTM1, as a reference to myotubular myopathy (MTM). Similarly, when researchers discovered the protein typically produced by that gene, they named it "myotubularin".

[edit] Current terminology of Myotubular Myopathy (MTM) versus Centronuclear Myopathy (CNM)

[edit] Muscle biopsy terminology from the pathology reports.

On muscle biopsy, nuclear material located predominantly in the center of the muscle cells is described as having any "myotubular" or "centronuclear" appearance. In terms of describing the muscle biopsy itself, "myotubular" or "centronuclear” are almost synonymous, and both terms point to the similar cellular-appearance among MTM and CNM. Thus, pathologists and treating physicians might still sometimes use those terms almost interchangeably, although increasingly researchers and clinicians are distinguishing between those phrases. Thus, synonymous use of the terms is falling out of favor.

In general, anyone with a clinical myopathy and a muscle biopsy showing a centronuclear (nucleus in the center of the muscle cell) appearance would be considered as having a centronuclear myopathy (CNM). Since there are a number of genetic abnormalities that can cause myopathy with a centronuclear appearance, it can be said that there are multiple centronuclear myopathies. Thus, some researchers use the plural form of the abbreviation, CNMs, to denote that centronuclear myopathy is not a single, homogeneous disorder, but instead there is a small group of myopathies sharing this centronuclear appearance. The most commonly diagnosed CNM is myotubular myopathy (MTM) and thus, MTM would probably be considered the most common sub-category of the centronuclear myopathies (CNMs). However, using muscle biopsy analysis alone, pathologists cannot reliably distinguish myotubular myopathy from other forms of centronuclear myopathies, and thus genetic testing is required for those purposes.

[edit] Terminology based on specific, identified genetic abnormalities

Since the muscle biopsy cannot distinguish among the centronuclear myopathies, genetic testing has become increasingly important for sub-categorizing and understanding the various centronuclear myopathies. Thus, many researchers are starting to reserve the term "myotubular myopathy" (MTM) for cases where the genetic test has come back positive for abnormalities (genetic mutations) at the MTM1 gene on the X chromosome (the MTM1 gene is located at site Xq28). The localization of the genetic abnormality to the X chromosome at site Xq28 was first reported in 1990 [5] and patients may now undergo genetic testing for this mutation [6]

Cases with a centronuclear (nucleus in the center) appearance on muscle biopsy but a negative (normal) genetic test for MTM1 would be referred to as centronuclear myopathy (until such time as a specific genetic site is identified to give more specific sub-classification).

[edit] Terminology based on X-linked versus Autosomal genetic inheritance pattern

Genetically inherited traits and conditions are often referred to based upon whether they are located on the "sex chromosomes" (the X or Y chromosomes) versus whether they are located on "autosomal" chromosomes (chromosomes other than the X or Y). Thus, genetically inherited conditions can be categorized as being sex-linked (e.g., X-linked) or autosomal. Females have a pair of two X-chromosomes while males only have a single X chromosome. Thus, a genetic abnormality located on the X chromosome is much more likely to cause clinical disease in a male (who inherently lacks the possibility of having the normal gene present on another X chromosome) than in a female (who inherently has another X chromosome, which might be a normal X chromosome and thus able to compensate for the one abnormal X chromosome).

Many clinicians and researchers will use the abbreviations XL-MTM, XLMTM or X-MTM to emphasize that the genetic abnormality for myotubular myopathy (MTM) is X-linked (XL), having been identified as occurring on the X chromosome. The specific gene on the X chromosome is referred to as MTM-1. It is theoretically possible that some cases of CNM may be caused by a genetic abnormality on the X chromosome, but located at a different site than the gene MTM1, but currently MTM1 is the only X-linked genetic mutation site identified for myotubular or centronuclear myopathy. Clinical suspicion for X-linked inheritance would be a disease affecting multiple boys (but no girls) and a pedigree chart showing inheritance only through the maternal (mother’s) side of each generation. To date, the only X-linked mutation site causing centronuclear myopathy is the MTM1 gene.

Centronuclear myopathies where the genetic abnormality is NOT located on a sex-linked chromosome (e.g., not located on the X chromosome) would be considered Autosomal. Autosomal genetic abnormalities can either be dominant or recessive (often referred to as AD for "autosomal dominant" or AR for "autosomal recessive").

[edit] Terminology based on Dominant versus Recessive genes

Most chromosomes occur in matched pairs, except for the sex chromosomes in males (who possess a single X chromosome and a single Y chromosome). Thus, humans have two copies of most genes (one copy inherited from the father and one copy inherited from the mother). If one copy of a specific gene is normal but the other copy is abnormal, the effect of the abnormal gene depends upon whether the gene is recessive or dominant. A "dominant" abnormality will exert its abnormal influence (e.g., causing a disease or medical condition) regardless of whether the other copy of the gene is normal or not. Conversely, a "recessive" abnormality will only cause disease if BOTH copies of the gene are abnormal.

[edit] Combining the Genetic Terms

Whether a genetic abnormality is dominant versus recessive is a separate distinction than the point as to whether the gene is located on an autosomal chromosome versus a sex-linked chromosome.

Thus, the possible combinations of categories are as follows:

  • X-linked recessive (such as MTM1; myotubular myopathy)
  • X-linked dominant (not known to exist for myotubular/centronuclear myopathies)
  • Autosomal recessive (specific genetic site not yet identified for centronuclear myopathy, but there is ongoing research in this area)
  • Autosomal dominant (such as DNM2 centronuclear myopathy)
  • Sporadic cases have also been reported where there is no previous family history (presumably due to a new mutation that was not present in either parent).

[edit] Genetic basis for gender differences in MTM/CNM

  • The X-linked form of MTM/CNM is the most commonly diagnosed type. X-linked means that the genetic abnormality responsible for the condition is located on the X chromosome. Since females receive two X-chromosomes, a recessive abnormality on one X chromosome can usually be compensated for by having a normal gene on the other X chromosome. Thus, while females can be "carriers" for an X-linked genetic abnormality, usually they will not be clinically affected themselves. Conversely, a genetic abnormality on a male’s only X chromosome has no normal X chromosome counterpart to compensate for it. Thus, almost all cases of X-linked MTM occur in boys/males.
    • There are two exceptions where it is possible for a female with a X-linked recessive genetic abnormality to have clinical symptoms: one is a "manifesting carrier" and the other is "X-inactivation."
      • A female may be a "manifesting carrier."[7] Unlike a typical carrier, who is unaffected by the disease, a "manifesting" carrier manifests (presents with) some of the same types of symptoms as the full-blown condition. A manifesting carrier usually has no noticeable problems at birth; symptoms show up later in life.
      • In X-inactivation, the female (who would otherwise just be a carrier, without any symptoms), actually presents with full-blown X-linked MTM. This happens because, although she has 2 copies of the X in her body [where one X is carrying the mutation for MTM and the other X is normal], her entire body chooses (for an unknown reason) to use the abnormal X (in other words, her body “inactivates” the normal X). Thus, she congenitally presents (is born with) MTM. [8] Normally, the body naturally elects to use the unaffected X, but in this case it does not. This is different from the “manifesting carrier” in that with X- inactivation, all of the cells in the body use the effected X, and these girls are born with all of the classic symptoms (severe hypotonia, hypoxia-requiring assistance with breathing, dolicocephaly, etc.) Unlike a manifesting carrier, a girl with X-inactivation may have noticeable problems at birth.
      • The distinctions of manifesting carriers and X-inactivation can not be sorted out without gene analysis, thus pointing to the importance of genetic testing for all individuals with myopathies that have not yet been genetically identified.
      • Thus, researchers point out that although MTM1 mutations most commonly cause problems in boys, these mutations can also can clinical myopathy in girls, for the reasons noted above. Thus, experts recommend that girls with myopathy and a muscle biopsy showing a centronuclear pattern should be tested for MTM1 mutations, just as boys are tested for this.[9]
  • "Autosomal" refers to genes that are NOT sex linked (e.g., those genes are NOT located on the X chromosome). Thus, autosomal genetic disorders may affect both males and females with relatively similar frequency. Within centronuclear myopathies, researchers have identified an autosomal dominant form at a gene called dynamin 2 (DNM2) on chromosome 19, and this particular condition is now referred to as dynamin 2 centronuclear myopathy (DNM2-CNM).

[edit] Incidence of Centronuclear Myopathies

The overall incidence (frequency) of myotubular myopathy and other centronuclear myopathies is not known. They are understood to be far less common than more well-known muscle disorders like Duchenne's muscular dystrophy.

Many patients with myotubular myopathy die in infancy prior to receiving a formal diagnosis. When possible, muscle biopsy and genetic testing may still be helpful even after a neonatal death, since the diagnostic information can assist with family planning and genetic counseling, as well as aiding in the accurate diagnosis of any relatives who might also have the same genetic abnormality.

Approximately 80% of males with a diagnosis of myotubular myopathy by muscle biopsy will have a mutation in MTM1 identifiable by genetic sequence analysis. [10].

[edit] Electrodiagnostic Testing (EMG and Nerve Studies)

  • Basic definitions: Electrodiagnostic (also called electrophysiologic) testing includes nerve conduction studies (also called NCS, which involves stimulating a peripheral motor or sensory nerve and recording the response) and needle electromyography (also called EMG, where a thin needle or pin-like electrode is inserted into the muscle tissue to look for abnormal electrical activity).
  • Distinguishing myopathy from neuropathy via electrodiagnostic testing: Unfortunately, most of the electrodiagnostic abnormalities seen in myopathies (muscle disorders) can also be seen in neuropathies (nerve disorders). Electrodiagnostic abnormalities common to BOTH myopathies AND neuropathies include "abnormal spontaneous activity" (e.g., fibrillations, positive sharp waves, etc.) on needle EMG and small amplitudes of the motor responses (compound muscle action potential, or CMAP) during nerve conduction studies. One difference is that many neuropathies cause abnormalities of sensory nerve studies, whereas myopathies purely involve the muscle, with the sensory nerves being spared (normal). The most important factor distinguishing a myopathy from a neuropathy on needle EMG is the careful analysis of the motor unit action potential (MUAP) size, shape, and recruitment pattern.
  • Distinguishing one myopathy from another myopathy via electrodiagnostic testing: Unfortunately, there is very substantial overlap between the electrodiagnostic findings the various types of of myopathy. Thus, electrodiagnostic testing can help distinguish neuropathy from myopathy, but is not effective at distinguishing which specific myopathy is present (hence the need for the muscle biopsy and perhaps subsequent genetic testing).
  • Further diagnostic testing, based on the results of the electrodiagnostic testing: Electrodiagnostic testing can help distinguish myopathies (muscle disorders) from neuropathies (nerve disorders), which can help with further work-up. For example, with a "floppy" (low muscle tone) infant, electrodiagnostic testing showing findings of neuropathy might help direct further diagnostic workup to look for causes of congenital neuropathies (such as undergoing the genetic testing for spinal muscular atrophy, also called SMA). Conversely, if electrodiagnostic testing in the low tone infant showed findings of myopathy, this might direct further diagnostic workup to include muscle biopsy and any genetic testing that is available for any myopathy that is clinically being considered in a given case.

[edit] Genetic Testing

Neither muscle biopsy nor electrodiagnostic testing can distinguish among the different types of centronuclear myopathies, and thus genetic testing is typically recommended and performed for all cases where the muscle biopsy shows a centronuclear (myotubular) appearance.

Currently, genetic testing is available for the X-linked form of myotubular myopathy known as MTM1. The testing is available through a very limited number of laboratories, such as the University of Chicago in the United States. [11]

Within a given group of relatives, the first case identified as having the genetic abnormality is considered the “index case”. Genetically testing the parents and other relatives can help establish whether the "index case" was due to a genetic abnormality that was inherited from the parents versus a spontaneous mutation (new mutation) during the embryonic development of the index case. Further, genetic testing of relatives may reveal individuals with the same genetic mutation but a much milder clinical (or sub-clinical) presentation. All of this is important information for family planning, so that relatives carrying the defective gene may receive counseling as to their likelihood of having offspring with the resultant myopathy.

For families with a known genetic mutation, prenatal testing is available by evaluating the fetus’s genetic material, obtained from the amniotic fluid or chorionic villus sampling.

For patients with a positive muscle biopsy but a genetic test that is negative for mutations at the MTM1 gene, there are a limited number of research labs worldwide working on research to identify the involved genes in the other forms of centronuclear myopathy.

Meanwhile, for the autosomal dominant form of CNM, in 2005 international researchers first reported that the involved mutation is at a gene called dynamin 2 (DNM2) on chromosome 19. However, genetic testing for this condition, now referred to as dynamin 2 centronuclear myopathy (DNM2-CNM), is not yet commercially available. Thus, such testing is currently only performed via a limited number of involved research labs.

[edit] Clinical presentation

As with other myopathies, the clinical manifestations of MTM/CNM are most notable for muscle weakness and associated disabilities. Congenital forms often present with neonatal low muscle tone, severe weakness, delayed developmental milestones (particularly gross motor milestones such as head control, crawling, and walking) and pulmonary complications (presumably due to weakness of the muscles responsible for respiration). X-linked myotubular myopathy was traditionally considered to be a fatal condition of infancy, with life expectancy of usually less than two years, but the literature is increasingly reporting MTM1 patients who are living much longer.

For example, while most truncating mutations of MTM1 cause the severe and early lethal phenotype, some missense mutations are associated with milder forms and prolonged survival (up to 54 years). [12] Thus, there appears to be substantial variability in the clinical severity for different genetic abnormalities at that same MTM1 gene. Further, there are published cases showing significant differences in clinical severity among relatives having the same genetic abnormality at that MTM1 gene.

Meanwhile, centronuclear myopathies typically have a milder presentation and a better prognosis in cases that do not involve the MTM1 gene (i.e., cases that where the genetic test for MTM1 is negative, meaning normal). Presumably, these cases represent abnormalities at other genetic sites. In 2005, an international collaboration of researchers discovered an autosomal (not X-linked) genetic abnormality responsible for an autosomal dominant form of centronuclear myopathy. [13] They identified the mutations at the gene dynamin 2 (DNM2 on chromosome 19, at site 19p13.2), and now such patients are referred to as having dynamin 2 centronuclear myopathy (abbreviated DNM2-CNM). A 2006 publication has indicated that patients with DNM2-CNM have a slowly progressive muscular weakness usually beginning in adolescence or early adulthood. That study reported 10 patients with DNM2-CNM, with an age range of 12 to 74 years.

Diagnostic workup is often coordinated by a treating neurologist. In the United States, care is often coordinated through clinics affiliated with the Muscular Dystrophy Association.

[edit] Treatment

Currently there is no cure for myotubular or centronuclear myopathies. Treatment often focuses on trying to maximize functional abilities and minimize medical complications.

Functional goals are often addressed through involvement by physicians specializing in Physical Medicine and Rehabilitation (Physiatry), and by physical therapists and occupational therapists.

While some patients with centronuclear myopathies remain ambulatory throughout adult life, others may never crawl or walk and may require wheelchair use for mobility. There is substantial variability in the degree of functional impairment among the various centronuclear myopathies.

Medical management generally involves vigilant efforts to prevent pulmonary complications, since lung infections can be fatal in patients lacking the muscle strength necessary to clear secretions via effective coughing. Indeed, lung infections are a common cause of death among patients with myopathies. Medical devices to assist with coughing can help patients maintain clear airways, avoiding mucous plugging and avoiding the need for tracheostomy tubes in most patients with myopathies. [14]

Monitoring for scoliosis is important, since weakness of the trunk muscles can lead to deviations in spinal alignment, with resultant compromise of respiratory function. Many patients with congenital myopathies may eventually require surgical treatment of scoliosis.

[edit] Educational interventions

In the United States, children with congenital myopathies often receive therapy services through Early Intervention Programs (EIP, providing services from birth to 3 years old) administered by the state of residence. After the child is 3 years old, Special Education services are provided under the federal Individuals with Disabilities Education Act (IDEA, with myopathies being eligible when classified under conditions causing muscular weakness). IDEA is meant to protect the rights of every disabled student to receive a free and appropriate public education (FAPE) in the least restrictive environment (ideally meaning integrated with able-bodied classmates).

Centronuclear myopathies involve pathology at the skeletal muscles, generally without brain involvement or cognitive deficits. Even so, the motor deficits (weakness and associated impairments) may impede in individual’s ability to access the educational curriculum (e.g., difficulties lifting or carrying books, difficulties grasping a writing instrument, endurance difficulties throughout the school day, etc.). Further, recurrent respiratory infections may result in missed school days. Ideally, parents, students, and school officials should work together to develop a comprehensive plan that will meet the student’s needs, as required under federal law.

[edit] Support Groups

Support groups for myotubular and centronuclear myopathies allow patients, families, and others to share common experiences, to exchange advice, to discuss the latest research advancements, and to network on a local, regional, national, and (with online Internet groups) even an international basis. The support groups may help members to relieve feelings of stress and isolation that can be associated with being effected by a very rare disease. Such networks may help interested persons stay abreast of current diagnostic and treatment options, and they may also learn of possibilities to help advance the research on this condition. [15] A number of online support groups are listed in the External Links section at the bottom of this wikipedia topic.

[edit] External links

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